1. Technical Field
The present invention relates generally to anti-IL-6 receptor (IL-6R) antibodies, compositions and methods of using same. The invention is more specifically related to anti-IL-6R antibodies and their manufacture and use. Such antibodies are useful, for example, in methods for treating any of a variety of inflammatory and oncological diseases.
2. Description of the Related Art
Interleukin-6 (IL-6) is a multi-functional cytokine that plays a central role in host defense mechanisms. Heinrich et al., Biochem. J. (1990) 26.5:621; Van Snick, J. Annu. Rev. Immunol. (1990) 8:253; and Himno et al., Immunol. Today (1990) 11:443. However, in a variety of human inflammatory, autoimmune, and neoplastic diseases, abnormal IL-6 production is observed and has been suggested to play a role in the pathogenesis of those diseases. Hirano et al., supra; Sehgal, P. B., Proc. Soc. Exp. Biol. Med. (1990) 195:183; Grau, G. E., Eur. Cytokine Net (1990) 1:203; Bauer et al., Ann. Hematol. (1991) 62:203; Campbell et al., J, Clin, Invest. (1991) 7:739; and Roodman et al., J. Clin. Invest. (1992) 89:46. Inhibitors of IL-6 bioactivity might thus be useful to study its role in disease and could have broad therapeutic applications.
IL-6 is produced by T cells, B cells, monocytes, fibroblasts, keratinocytes, endothelial cells, mesangial cells, and several tumor cell lines. IL-6 induces growth of T cells and differentiation of cytotoxic T cells by augmenting the expression of IL-2 receptor and the production of IL-2. IL-6 acts synergistically with IL-3 to support the formation of multilineage blast cell colonies in hematopoiesis and induces differentiation of macrophages, megakaryocytes, and osteoclasts. In the acute-phase reaction, IL-6 stimulates hepatocytes to produce acute-phase proteins such as C-reactive protein (CRP), fibrinogen, α1-antitrypsin and serum amyloid A. IL-6 also causes leukocytosis and fever when administered in vivo and also acts as a growth factor for renal mesangial cells, epidermal keratinocytes, and various types of tumor cells, for example, in plasmacytoma, multiple myeloma, and renal cell carcinoma.
IL-6 overproduction is involved in sepsis (Starnes, Jr., H. F. et al., J. Immunol. (1990) 145:4185), and is also implicated in multiple myeloma, or plasma cell leukemia (Klein, B. et al., Blood (1991) 78:1198). Other diseases include bone resorption (osteoporosis) (Roodman, G. D. et al., J., Clin, Invest. (1992) 89:46; Jilka, R. L. et al., Science (1992) 257:88-91), cachexia (Strassman, G. et al., J. Clin. Invest. (1992) 89:1681), psoriasis, systemic-onset juvenile idiopathic arthritis, systemic lupus erythematosus, mesangial proliferative glomerulonephritis, renal cell carcinoma, Kaposi's sarcoma, rheumatoid arthritis (Eur. J. Immunol. 18, 1797-1801, 1988; Arthritis Rheum. 31, 784-788, 1988; Ann. Rheum. Dis. 52, 232-234, 1993), hyper gammaglobulinemia (Grau, G. E. et al., J. Exp. Meal. (1990) 172:1505), Castleman's disease, IgM gammopathy, cardiac myxoma and autoimmune insulin-dependent diabetes (Campbell, I. L. et al., J, Clin, Invest., (1991) 87:739). Rat anti-mouse IL-6R antibody prevented the development of collagen-induced arthritis (CIA) in DBA/1J mice and anti-human IL-6 antibody was effective in both prevention and treatment of a monkey CIA model. This evidence suggest that IL-6 plays an essential role in the pathogenisis of arthritis and support the utility of these animal models for the study of arthritis and the therapeutic efficacy of anti-IL-6 or IL-6R treatments (Arthritis Rheum. 41, 2117-2121, 1998; Clin Immunol. 2001 March; 98(3):319-26; Biol Pharm Bull. 2008 June; 31(6):1159-63).
IL-6 functions through interaction with at least two specific receptors on the surface of target cells. Taga et al., J. Exp. Med. (1987) 166:967; and Coulie et al., Eur. J. Immunol, (1987) 17:1435. The cDNAs for these two receptor chains have been cloned, and they code for two transmembrane glycoproteins: the 80 kDa IL-6 receptor “IL-6R”) and a 130 kDa glycoprotein called “gp130”. Yamasaki et al., Science (1988) 241:825; and Hibi et al., Cell (1990) 63:1149. IL-6 interacts with these glycoproteins following a unique mechanism. First, IL-6R binds to IL-6 with low affinity (Kd=about 1 nM) without triggering a signal. Taga et al., Cell (1989) 58:573. The IL-6/IL-6R complex subsequently associates with gp130, which transduces the signal. Hibi et al., supra; and Taga et al., supra. Gp130 itself has no affinity for IL-6 in solution, but stabilizes the IL-6/IL-6R complex on the membrane, resulting in high affinity binding of IL-6 (Kd=about 10 pM). Hibi et al., supra. It was recently found that gp130 is also a low affinity receptor for oncostatin M and an affinity converter for the LIF receptor (Gearing, D. P. et al., Science (1992) 255:1434).
One method for neutralization of IL-6 activity is the use of antibodies that specifically bind to IL-6. Neutralizing monoclonal antibodies (MAbs) to IL-6 can be divided in two groups, based on the recognition of two distinct epitopes on the IL-6 molecule, designated Site I and Site II. Site I is a conformational epitope composed of both amino terminal and carboxy terminal portions of the IL-6 molecule. Brakenhoff et al. (1990, J. Immunol. 145:561-568).
Another way to neutralize IL-6 activity is to inhibit the ligand-receptor interactions by binding to and blocking IL-6R. This invention provides these and other advantages as described further herein.